Process for the recovery of d-p-hydroxyphenylglycine and ammonium chloride from the crystallization mother liquor

Abstract

The application discloses a method for recovering D-p-hydroxyphenylglycine and ammonium chloride from a crystallization mother liquor, which comprises the following steps: removing the protein and pigment impurities remaining in the D-p-hydroxyphenylglycine crystallization mother liquor by using an ultrafiltration membrane; then, the solubility difference of D-p-hydroxyphenylglycine and ammonium chloride is utilized, i.e. under the condition of higher temperature, the mother liquor is concentrated by evaporation under reduced pressure, D-p-hydroxyphenylglycine is crystallized and precipitated, and D-p-hydroxyphenylglycine is recovered; then, under the condition of reduced temperature, ammonium chloride is crystallized and precipitated from the concentrated mother liquor, and ammonium chloride is recovered. The application ingeniously utilizes the crystallization under two kinds of temperatures, and realizes the comprehensive recovery of the two effective components in the mother liquor; the recovery process does not introduce new substances, and the use of high-risk, high-energy consumption and high-pollution process steps is abandoned; the whole process is safe, energy-saving, environment-friendly and low in cost, the recovery product has high yield and good quality, and therefore, the process is very suitable for industrialization promotion.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of pharmacy, and relates to a method for recovering D-p-hydroxylphenylglycine and ammonium chloride from a crystallization mother liquor, more particularly, to a method for recovering D-p-hydroxylphenylglycine and ammonium chloride from a crystallization mother liquor in the enzymatic synthesis of D-p-hydroxylphenylglycine. BACKGROUND

[0002] D-p-hydroxylphenylglycine (D-p-HPG) is an important pharmaceutical intermediate in the synthesis of antibiotics, and is mainly used for the synthesis of D-p-hydroxylphenylglycine methyl ester, which is a side chain compound in the enzymatic synthesis of amoxicillin.

[0003] At present, the preparation methods of D-p-hydroxylphenylglycine mainly include enzymatic method and chemical method. The enzymatic method mainly uses p-hydroxyphenylhydrazine as a substrate, and uses D-hydrazine enzyme and D-carbamoyl hydrolase to catalyze the conversion of p-hydroxyphenylhydrazine into D-p-hydroxylphenylglycine. In the conversion process, D-p-hydroxylphenylglycine is gradually precipitated. After the enzymatic reaction is completed, hydrochloric acid is added to dissolve the precipitated D-p-hydroxylphenylglycine. After filtration and removal of impurities, ammonia water is added to adjust the pH to 4.5-5.5, and D-p-hydroxylphenylglycine is precipitated and crystallized. After filtration and drying, the D-p-hydroxylphenylglycine product with qualified quality is obtained. The mother liquor after the separation of D-p-hydroxylphenylglycine crystals is the crystallization mother liquor in the enzymatic synthesis of D-p-hydroxylphenylglycine. The above-mentioned enzymatic process gradually becomes the mainstream production method of D-p-hydroxylphenylglycine due to its simple process, less pollution, low cost, high product quality and other advantages.

[0004] As described above, a large amount of hydrochloric acid and ammonia water is consumed in the crystallization process after the above-mentioned enzymatic reaction, and therefore a large amount of ammonium chloride exists in the enzymatic crystallization system, which leads to the salt dissolution phenomenon in the residual crystallization mother liquor after the preparation and crystallization separation of D-p-hydroxylphenylglycine, and further seriously affects the yield of the product. Generally, in the crystallization mother liquor, the concentration of D-p-hydroxylphenylglycine is 15-20 g / L, the concentration of ammonium chloride is 140-160 g / L, the pH value is 4.5-5.5, and the conductivity is 150-200 ms / cm. Therefore, the research on the post-treatment process of the residual crystallization mother liquor in the enzymatic synthesis of D-p-hydroxylphenylglycine has great economic and environmental protection significance, and is also a project that each manufacturer is committed to research.

[0005] Chinese patent document CN113214103A discloses a subsequent treatment method for enzyme synthesis of D-p-hydroxyphenylglycine, which includes recovering monovalent salt by using nanofiltration and concentrating and evaporating dry, recovering trivalent salt by using electrodialysis and concentrating and evaporating dry, and recycling the remaining desalination liquid rich in D-p-hydroxyphenylglycine. This method realizes the recovery of salt components in the mother liquor, but does not realize the recovery of D-p-hydroxyphenylglycine. This method has obvious disadvantages. A large amount of purified water is needed to remove monovalent salt in the mother liquor by using nanofiltration membrane, and concentrating and evaporating these large amounts of water will pay a high power cost. In the process of washing the mother liquor with purified water, part of the D-p-hydroxyphenylglycine in the mother liquor will also pass through the nanofiltration membrane, which will cause product loss on the one hand, and will also affect the quality of the recovered monovalent salt on the other hand. The use of the power-hungry electrodialysis method to remove trivalent salt in the mother liquor will lead to a sharp rise in recovery cost, and the recovered trivalent salt will be mixed with part of the monovalent salt and D-p-hydroxyphenylglycine, which will greatly reduce its quality. Therefore, the method reported in this patent document does not realize the recovery of D-p-hydroxyphenylglycine, but uses the desalination liquid containing D-p-hydroxyphenylglycine in step (2), which will affect the quality of the normally produced D-p-hydroxyphenylglycine product.

[0006] In addition, Chinese patent documents CN112479909A and CN112029812A both use the electrodialysis method to recover D-p-hydroxyphenylglycine, which results in a huge power consumption and high recovery cost.

[0007] Chinese patent document CN111393315A discloses a method for recovering D-p-hydroxyphenylglycine from the crystallization mother liquor of enzyme-synthesized D-p-hydroxyphenylglycine, which uses macroporous resin adsorption to recover D-p-hydroxyphenylglycine. In this method, a large amount of industrial wastewater will be generated due to the use of resin, which needs subsequent treatment, and a large amount of hydrochloric acid and ammonia water needs to be introduced into the process, which will further greatly increase the production cost of D-p-hydroxyphenylglycine.

[0008] In summary, there is a continuous need for research, improvement and optimization of the recovery treatment process of the crystallization mother liquor of enzyme-synthesized D-p-hydroxyphenylglycine, in order to seek a recovery process that is reasonable in process design, easy to operate, good in recovery effect, more economical and suitable for industrialization. SUMMARY

[0009] TECHNICAL PROBLEM

[0010] Therefore, the present application is made to solve the above-mentioned problems in the prior art. The purpose of the present application is to provide a method for recovering D-p-hydroxyphenylglycine and ammonium chloride from the crystallization mother liquor of enzyme-synthesized D-p-hydroxyphenylglycine, which is reasonable in process design, easy to operate, good in recovery effect, excellent in product quality, more economical and suitable for industrialization.

[0011] Technical solution

[0012] In order to achieve the above-mentioned purpose of the present application, the technical solution adopted by the present application is as follows: first, the ultrafiltration membrane is used to remove the protein and pigment impurities remaining in the crystallization mother liquor of the enzyme-synthesized D-p-hydroxyphenylglycine; then, the solubility difference between D-p-hydroxyphenylglycine and ammonium chloride is utilized, i.e. under the condition of higher temperature, the mother liquor is concentrated by evaporation under reduced pressure, D-p-hydroxyphenylglycine is crystallized and precipitated, and D-p-hydroxyphenylglycine is recovered; then, under the condition of reduced temperature, ammonium chloride is crystallized and precipitated, and ammonium chloride is recovered; the above-mentioned process of recovering D-p-hydroxyphenylglycine under higher temperature and recovering ammonium chloride under reduced temperature is repeated for the separated mother liquor, and most of the D-p-hydroxyphenylglycine and ammonium chloride in the mother liquor are recovered after the treatment.

[0013] According to the present application, the present application provides a method for recovering D-p-hydroxyphenylglycine and ammonium chloride from the crystallization mother liquor of the enzyme-synthesized D-p-hydroxyphenylglycine, which comprises the following steps:

[0014] (1) Primary recovery of D-p-hydroxyphenylglycine and ammonium chloride

[0015] The crystallization mother liquor of the enzyme-synthesized D-p-hydroxyphenylglycine is subjected to ultrafiltration by using an ultrafiltration membrane to obtain an ultrafiltrated mother liquor; then, the ultrafiltrated mother liquor is concentrated by evaporation under reduced pressure at a temperature of 50-90°C to 2 times or more, D-p-hydroxyphenylglycine is crystallized and precipitated, and filtration is carried out at this temperature to obtain D-p-hydroxyphenylglycine and a filtered mother liquor; the filtered mother liquor is subjected to crystallization and precipitation of ammonium chloride at a reduced temperature of 5-25°C, and filtration is carried out at this temperature to obtain ammonium chloride and a primary mother liquor after filtration.

[0016] (2) Secondary recovery of D-p-hydroxyphenylglycine and ammonium chloride

[0017] The primary mother liquor obtained in the step (1) is concentrated by evaporation under reduced pressure at a temperature of 50-90°C to 1.5 times or more, D-p-hydroxyphenylglycine is crystallized and precipitated, and filtration is carried out at this temperature to obtain D-p-hydroxyphenylglycine and a filtered mother liquor; the filtered mother liquor is subjected to crystallization and precipitation of ammonium chloride at a reduced temperature of 5-25°C, and filtration is carried out at this temperature to obtain ammonium chloride and a secondary mother liquor after filtration.

[0018] Beneficial effects

[0019] Compared with the prior art, the method has the advantages that: the difference in solubility of D-p-hydroxyphenylglycine and ammonium chloride is innovatively utilized, i.e. under the condition of high temperature, the mother liquor is concentrated by evaporation under reduced pressure, D-p-hydroxyphenylglycine is crystallized and precipitated, and D-p-hydroxyphenylglycine is recovered, and then under the condition of low temperature, ammonium chloride is crystallized and precipitated from the concentrated mother liquor, and ammonium chloride is recovered, the crystallization under two temperatures is ingeniously utilized, and the comprehensive recovery of the two effective components in the crystallization mother liquor of the enzyme-synthesized D-p-hydroxyphenylglycine is realized. The recovery process does not introduce new substances, and the use of high-risk, high-energy-consumption and high-pollution process steps is abandoned. The whole process is safe, energy-saving, environmentally friendly and low in cost, and the recovery product has high yield and good quality. Therefore, the process is very suitable for industrialization and popularization. The use of the method of the present application can recover D-p-hydroxyphenylglycine and ammonium chloride in the mother liquor, which not only can increase new economic benefits, but also can avoid damage to the environment, and has obvious practical significance. BRIEF DESCRIPTION OF DRAWINGS

[0020] Figure 1 is a process flow chart of the method for recovering D-p-hydroxyphenylglycine and ammonium chloride from the crystallization mother liquor of the enzyme-synthesized D-p-hydroxyphenylglycine according to an embodiment of the present application;

[0021] Figure 2 is a process flow chart of the method for recovering D-p-hydroxyphenylglycine and ammonium chloride from the crystallization mother liquor of the enzyme-synthesized D-p-hydroxyphenylglycine according to another embodiment of the present application. DETAILED DESCRIPTION

[0022] Hereinafter, the method for recovering D-p-hydroxyphenylglycine and ammonium chloride from the crystallization mother liquor of the enzyme-synthesized D-p-hydroxyphenylglycine of the present application will be described in more detail to help understand the present application.

[0023] Figure 1 is a process flow chart of the method for recovering D-p-hydroxyphenylglycine and ammonium chloride from the crystallization mother liquor of the enzyme-synthesized D-p-hydroxyphenylglycine according to an embodiment of the present application, according to an embodiment of the present application, in the method for recovering D-p-hydroxyphenylglycine and ammonium chloride from the crystallization mother liquor of the present application, in the step (1) of the first recovery of D-p-hydroxyphenylglycine and ammonium chloride, the crystallization mother liquor of the enzyme-synthesized D-p-hydroxyphenylglycine is subjected to ultrafiltration by using an ultrafiltration membrane to obtain an ultrafiltrated mother liquor; then the ultrafiltrated mother liquor is concentrated by using the way of evaporation under reduced pressure at a temperature of 50-90°C to 2 times or more, D-p-hydroxyphenylglycine is crystallized and precipitated, and at this temperature, filtration is performed to obtain D-p-hydroxyphenylglycine and a filtered mother liquor; the filtered mother liquor is subjected to crystallization and precipitation of ammonium chloride at a reduced temperature of 5-25°C, and at this temperature, filtration is performed to obtain ammonium chloride and a first filtered mother liquor.

[0024] As mentioned above, in the crystallization mother liquor of the enzymatic synthesis of D-p-hydroxyphenylglycine, the concentration of D-p-hydroxyphenylglycine is usually 15-20 g / L, the concentration of ammonium chloride is 140-160 g / L, the pH value is 4.5-5.5, and the conductivity is 150-200 ms / cm.

[0025] The crystallization mother liquor of the enzymatic synthesis of D-p-hydroxyphenylglycine is subjected to ultrafiltration using an ultrafiltration membrane. The ultrafiltration membrane can be an ultrafiltration membrane with a molecular weight cut-off of 1000-2500 Dalton, more preferably an ultrafiltration membrane with a molecular weight cut-off of 1000-1500 Dalton, and most preferably an ultrafiltration membrane with a molecular weight cut-off of 1000 Dalton. The ultrafiltration is used to remove impurities and pigments in the mother liquor. In this process, only D-p-hydroxyphenylglycine and ammonium chloride pass through the membrane, while impurities and pigment components are retained and removed.

[0026] Then, the ultrafiltrated mother liquor is concentrated by more than 2 times at a temperature of 50-90°C by vacuum distillation. D-p-hydroxyphenylglycine crystallizes at this temperature, and is filtered to obtain D-p-hydroxyphenylglycine and the filtered mother liquor. Preferably, the temperature during the vacuum distillation concentration process is maintained in the range of 60-80°C, and the vacuum degree is controlled to be ≤-0.080 MPa. In this temperature and vacuum degree range, the concentration of the mother liquor can be smoothly carried out.

[0027] The ultrafiltrated mother liquor is concentrated by more than 2 times, preferably 2.5-4 times. Under this concentration multiple, the quality of the recovered product can be ensured. This is mainly because the solubility of D-p-hydroxyphenylglycine in water does not change much with temperature, so D-p-hydroxyphenylglycine does not produce a concentration enrichment effect during concentration, but gradually crystallizes from the concentrated solution as the concentration multiple increases. The solubility of ammonium chloride in water increases significantly with temperature, so ammonium chloride produces a concentration enrichment effect during concentration and does not crystallize as the concentration multiple increases.

[0028] After concentration, the D-p-hydroxyphenylglycine crystallized in the concentrated solution is collected by conventional filtration techniques. The temperature of the concentrated solution during the filtration and collection process should be maintained within the temperature range of the vacuum distillation concentration described above, to avoid the crystallization of ammonium chloride and thus affect the product quality of D-p-hydroxyphenylglycine. Then, the D-p-hydroxyphenylglycine product meeting the quality standards is obtained by removing the water using conventional drying methods.

[0029] Next, the filtered mother liquor is cooled to 5-25°C, preferably 10-20°C. At this temperature, a large amount of ammonium chloride crystals will be precipitated, which are filtered and collected with the primary mother liquor. The ammonium chloride is dried to obtain the ammonium chloride product.

[0030] In this case, in step (1), D-p-hydroxyphenylglycine and ammonium chloride are recovered at one time, and in the obtained primary mother liquor, the concentration of D-p-hydroxyphenylglycine is generally 20-25 g / L, the concentration of ammonium chloride is 280-320 g / L, the pH is 4.5-5.5, and the conductivity is 300-400 ms / cm.

[0031] As shown in the figure, according to one embodiment of the present application, in the method for recovering D-p-hydroxyphenylglycine and ammonium chloride from a crystallization mother liquor of the present application, in the secondary recovery of D-p-hydroxyphenylglycine and ammonium chloride in step (2), the primary mother liquor obtained in step (1) is concentrated to more than 1.5 times by vacuum distillation at a temperature of 50-90°C, D-p-hydroxyphenylglycine is crystallized out, and the filtrate is obtained by filtration at this temperature; the filtrate is cooled to a temperature of 5-25°C, ammonium chloride is crystallized out, and the secondary filtrate is obtained by filtration at this temperature. Figure 1

[0032] Specifically, the primary mother liquor obtained in step (1) is concentrated to more than 1.5 times, preferably 1.5-2.5 times, by vacuum distillation at a temperature of 50-90°C, preferably 60-80°C, with a vacuum degree controlled at ≤-0.080 MPa, D-p-hydroxyphenylglycine is crystallized out, and the filtrate is obtained by filtration at this temperature. That is, after concentration, the D-p-hydroxyphenylglycine crystallized out in the concentrated solution is collected by filtration using conventional filtration techniques, and the temperature of the concentrated solution also needs to be maintained within the temperature range of the vacuum distillation concentration during the filtration collection, so as to avoid the crystallization of ammonium chloride in the concentrated solution and thus affect the product quality of D-p-hydroxyphenylglycine. Then, the D-p-hydroxyphenylglycine product meeting the quality standards is obtained after removal of water by conventional drying means.

[0033] Next, the filtrate is cooled to a temperature of 5-25°C, preferably 10-20°C, and a large amount of ammonium chloride crystals are crystallized out at this temperature, and the crystallized ammonium chloride and the secondary filtrate are collected by filtration, and the ammonium chloride product is obtained after removal of water by drying.

[0034] In this case, in step (2), D-p-hydroxyphenylglycine and ammonium chloride are recovered at one time, and in the obtained secondary mother liquor, the concentration of D-p-hydroxyphenylglycine is generally 20-25 g / L, the concentration of ammonium chloride is 280-320 g / L, the pH is 4.5-5.5, and the conductivity is 300-400 ms / cm. According to needs, the secondary mother liquor can be used in step (1) after appropriate pretreatment, such as decolorization with activated carbon, and combined in the crystallization mother liquor of the enzymatic synthesis of D-p-hydroxyphenylglycine in an appropriate ratio.​

[0035] Figure 2 is a process flow chart of the method for recovering D-p- hydroxyphenylglycine and ammonium chloride from the crystallization mother liquor of enzymatically synthesized D-p- hydroxyphenylglycine according to another embodiment of the present application, the method for recovering D-p- hydroxyphenylglycine and ammonium chloride from the crystallization mother liquor of the present application can further comprise three recoveries of D-p-hydroxyphenylglycine and ammonium chloride, i.e. step (3): the secondary mother liquor obtained in the above step (2) is concentrated to more than 1.5 times at a temperature of 50-90°C by vacuum distillation, D-p-hydroxyphenylglycine is crystallized out, and the filtrate is obtained at this temperature; the filtrate is cooled to a temperature of 5-25°C, ammonium chloride is crystallized out, and the filtrate is obtained at this temperature; and the D-p-hydroxyphenylglycine and ammonium chloride are recovered.

[0036] Specifically, the secondary mother liquor obtained in the above step (2) is concentrated to more than 1.5 times, preferably 1.5-2.5 times, at a temperature of 50-90°C, preferably 60-80°C, under a vacuum degree of ≤-0.080 MPa, D-p-hydroxyphenylglycine is crystallized out, and the filtrate is obtained at this temperature. At this time, the mass of the D-p-hydroxyphenylglycine recovered in the third recovery can be deviated, and a small amount of purified water at 60-80°C can be used to rinse the D-p-hydroxyphenylglycine filter cake as needed, and then the D-p-hydroxyphenylglycine product meeting the quality standard is obtained after drying to remove water.

[0037] Next, the filtrate is cooled to a temperature of 5-25°C, preferably 10-20°C, and a large amount of ammonium chloride crystals are crystallized out at this temperature, and the crystallized ammonium chloride and the tertiary mother liquor are collected, and the ammonium chloride product is obtained after drying to remove water.

[0038] The washing water and the tertiary mother liquor collected after rinsing the D-p-hydroxyphenylglycine filter cake in the step (3) still contain a large amount of D-p-hydroxyphenylglycine and ammonium chloride, and the washing water and the tertiary mother liquor can be used in the step (1) after being appropriately pretreated, e.g. decolorized by activated carbon, and combined with the crystallization mother liquor of enzymatically synthesized D-p-hydroxyphenylglycine in an appropriate ratio.

[0039] The method for recovering D-p-hydroxyphenylglycine and ammonium chloride from the crystallization mother liquor of the present application will be described more specifically by examples below, but the scope of protection of the present application is not limited to these examples.

[0040] Example 1

[0041] (1) First recovery of D-p-hydroxyphenylglycine and ammonium chloride

[0042] The crystallization mother liquor of 50 L after crystallization separation of D-p-hydroxyphenylglycine was taken, wherein the concentration of D-p-hydroxyphenylglycine was 17 g / L, the concentration of ammonium chloride was 148 g / L, the pH was 5.1, and the conductivity was 185 ms / cm. The crystallization mother liquor was subjected to ultrafiltration using an ultrafiltration membrane with a molecular weight cut-off of 1000 daltons to remove the impurities and pigments in the above mother liquor to obtain an ultrafiltrated mother liquor; then the mother liquor was heated to 80°C and the vacuum degree was controlled to be ≤-0.080 MPa, under the condition, the concentrated solution was concentrated by 3.4 times under reduced pressure, D-p-hydroxyphenylglycine was crystallized out, and the concentrated solution was filtered while hot at 80°C to obtain 512 g of D-p-hydroxyphenylglycine with a yield of 60.2% and a content of 99.2%, and a specific optical rotation of -158° (c=1, 1N HCl).

[0043] Then, the mother liquor remaining after separation of D-p-hydroxyphenylglycine was cooled to 20°C, ammonium chloride was crystallized out, and 2892 g of ammonium chloride was collected by filtration with a yield of 39.1%. The first mother liquor of 13.5 L was collected, wherein the concentration of D-p-hydroxyphenylglycine was 23 g / L, the concentration of ammonium chloride was 312 g / L, the pH was 4.9, and the conductivity was 374 ms / cm.

[0044] (2) Second recovery of D-p-hydroxyphenylglycine and ammonium chloride

[0045] Then, the first mother liquor of 13.5 L was continuously heated to 80°C and the vacuum degree was controlled to be ≤-0.080 MPa, under the condition, the concentrated solution was concentrated by 1.7 times under reduced pressure, D-p-hydroxyphenylglycine was crystallized out, and the concentrated solution was filtered while hot at 80°C to obtain 116 g of D-p-hydroxyphenylglycine with a yield of 13.6% and a content of 99.0%, and a specific optical rotation of -157° (c=1, 1N HCl).

[0046] Then, the mother liquor remaining after separation of D-p-hydroxyphenylglycine was cooled to 20°C, ammonium chloride was crystallized out, and 2892 g of ammonium chloride was collected by filtration with a yield of 39.1%. The first mother liquor of 13.5 L was collected, wherein the concentration of D-p-hydroxyphenylglycine was 23 g / L, the concentration of ammonium chloride was 312 g / L, the pH was 4.9, and the conductivity was 374 ms / cm.

[0047] (3) Third recovery of D-p-hydroxyphenylglycine and ammonium chloride

[0048] The second mother liquor 7.3 L was then heated to 80°C and the vacuum was controlled at ≤ -0.080 MPa. Under this condition, the second mother liquor was concentrated by 2 times to precipitate D-p-hydroxyphenylglycine. The concentrated solution was filtered while hot at 80°C and the filter cake was washed with a small amount of purified water at 80°C to obtain 97.7 g of D-p-hydroxyphenylglycine with a yield of 11.5% and a content of 98.8%, and a specific optical rotation of -157° (c = 1, 1N HCl).

[0049] Then, the mother liquor remaining after the separation of D-p-hydroxyphenylglycine was cooled to 20°C to precipitate ammonium chloride. The ammonium chloride was collected by filtration to obtain 1128 g of ammonium chloride with a yield of 15.2%. The three mother liquors 3.2 L were collected, wherein the concentration of D-p-hydroxyphenylglycine was 21.5 g / L, the concentration of ammonium chloride was 319 g / L, the pH was 4.8, and the conductivity was 376 ms / cm.

[0050] In summary, without considering the three mother liquors and the washing liquid, the total yield of D-p-hydroxyphenylglycine was 85.4% with a content of more than 98.8%, and the total yield of ammonium chloride was 78.1%.

[0051] Example 2

[0052] (1) First recovery of D-p-hydroxyphenylglycine and ammonium chloride

[0053] The crystallization mother liquor 50 L after the separation of D-p-hydroxyphenylglycine was taken, wherein the concentration of D-p-hydroxyphenylglycine was 15 g / L, the concentration of ammonium chloride was 152 g / L, the pH was 4.9, and the conductivity was 188 ms / cm. The crystallization mother liquor was subjected to ultrafiltration using an ultrafiltration membrane with a molecular weight cut-off of 1000 daltons to remove the impurities and pigments in the mother liquor to obtain an ultrafiltrated mother liquor. Then, the ultrafiltrated mother liquor was heated to 60°C and the vacuum was controlled at ≤ -0.080 MPa. Under this condition, the ultrafiltrated mother liquor was concentrated by 3.0 times to precipitate D-p-hydroxyphenylglycine. The concentrated solution was filtered while hot at 60°C to obtain 385 g of D-p-hydroxyphenylglycine with a yield of 51.3% and a content of 99.3%, and a specific optical rotation of -158° (c = 1, 1N HCl).

[0054] Then, the mother liquor remaining after the separation of D-p-hydroxyphenylglycine was cooled to 20°C to precipitate ammonium chloride. The ammonium chloride was collected by filtration to obtain 1128 g of ammonium chloride with a yield of 15.2%. The three mother liquors 3.2 L were collected, wherein the concentration of D-p-hydroxyphenylglycine was 21.5 g / L, the concentration of ammonium chloride was 319 g / L, the pH was 4.8, and the conductivity was 376 ms / cm.

[0055] (2) Second recovery of D-p-hydroxyphenylglycine and ammonium chloride

[0056] The primary mother liquor 15.7 L was then heated to 60°C and the vacuum was controlled at < -0.080 MPa. Under these conditions, the primary mother liquor was concentrated by 1.5 times. D-p-hydroxyphenylglycine was crystallized and precipitated. The concentrated solution was filtered while hot at 60°C. D-p-hydroxyphenylglycine 120 g was obtained with a yield of 16.0% and a content of 99.1%. The specific optical rotation was -158° (c = 1, 1N HCl).

[0057] The primary mother liquor 15.7 L was then heated to 60°C and the vacuum was controlled at < -0.080 MPa. Under these conditions, the primary mother liquor was concentrated by 1.5 times. D-p-hydroxyphenylglycine was crystallized and precipitated. The concentrated solution was filtered while hot at 60°C. D-p-hydroxyphenylglycine 120 g was obtained with a yield of 16.0% and a content of 99.1%. The specific optical rotation was -158° (c = 1, 1N HCl).

[0058] 3) Third recovery of D-p-hydroxyphenylglycine and ammonium chloride

[0059] The primary mother liquor 15.7 L was then heated to 60°C and the vacuum was controlled at < -0.080 MPa. Under these conditions, the primary mother liquor was concentrated by 1.5 times. D-p-hydroxyphenylglycine was crystallized and precipitated. The concentrated solution was filtered while hot at 60°C. D-p-hydroxyphenylglycine 120 g was obtained with a yield of 16.0% and a content of 99.1%. The specific optical rotation was -158° (c = 1, 1N HCl).

[0060] The primary mother liquor 15.7 L was then heated to 60°C and the vacuum was controlled at < -0.080 MPa. Under these conditions, the primary mother liquor was concentrated by 1.5 times. D-p-hydroxyphenylglycine was crystallized and precipitated. The concentrated solution was filtered while hot at 60°C. D-p-hydroxyphenylglycine 120 g was obtained with a yield of 16.0% and a content of 99.1%. The specific optical rotation was -158° (c = 1, 1N HCl).

[0061] In summary, without considering the third recovery of mother liquor and washing liquid, the total yield of D-p-hydroxyphenylglycine was 80.9% with a content of more than 99.0%. The total yield of ammonium chloride was 72.0%.

[0062] Example 3

[0063] (1) First recovery of D-p-hydroxyphenylglycine and ammonium chloride

[0064] The crystallization mother liquor 50 L after the crystallization separation of D-p-hydroxyphenylglycine was taken, wherein the concentration of D-p-hydroxyphenylglycine was 18 g / L, the concentration of ammonium chloride was 158 g / L, the pH was 5.0, and the conductivity was 195 ms / cm. The crystallization mother liquor was subjected to ultrafiltration using an ultrafiltration membrane with a molecular weight cut-off of 1000 daltons to remove the impurities and pigments in the above mother liquor to obtain an ultrafiltrated mother liquor. Then, the mother liquor was heated to 80°C and the vacuum degree was controlled to be ≤-0.080 MPa, and under the condition, the concentration was carried out 3.2 times, D-p-hydroxyphenylglycine was crystallized out, and the concentrated solution was filtered while hot at 80°C to obtain 526 grams of D-p-hydroxyphenylglycine, with a yield of 58.4%, a content of 99.2%, and a specific optical rotation of -158° (c=1, 1N HCl).

[0065] Then, the mother liquor remaining after the separation of D-p-hydroxyphenylglycine was cooled to 10°C, ammonium chloride was crystallized out, and ammonium chloride was collected by filtration to obtain 3454 grams of ammonium chloride, with a yield of 43.7%. The first mother liquor 14.2 L was collected, wherein the concentration of D-p-hydroxyphenylglycine was 24 g / L, the concentration of ammonium chloride was 285 g / L, the pH was 4.9, and the conductivity was 345 ms / cm.

[0066] (2) Second recovery of D-p-hydroxyphenylglycine and ammonium chloride

[0067] Then, the first mother liquor 14.2 L was continuously heated to 80°C and the vacuum degree was controlled to be ≤-0.080 MPa, and under the condition, the concentration was carried out 1.8 times under reduced pressure, D-p-hydroxyphenylglycine was crystallized out, and the concentrated solution was filtered while hot at 80°C to obtain 135 grams of D-p-hydroxyphenylglycine, with a yield of 15.0%, a content of 99.1%, and a specific optical rotation of -158° (c=1, 1N HCl).

[0068] Then, the mother liquor remaining after the separation of D-p-hydroxyphenylglycine was cooled to 10°C, ammonium chloride was crystallized out, and ammonium chloride was collected by filtration to obtain 1456 grams of ammonium chloride, with a yield of 18.4%. The second mother liquor 7.3 L was collected, wherein the concentration of D-p-hydroxyphenylglycine was 23 g / L, the concentration of ammonium chloride was 289 g / L, the pH was 4.8, and the conductivity was 352 ms / cm.

[0069] (3) Third recovery of D-p-hydroxyphenylglycine and ammonium chloride

[0070] Finally, the secondary mother liquor 7.3 L was heated to 80 °C and the vacuum was controlled at ≤-0.080 MPa. The concentrated solution was concentrated twice under reduced pressure, and D-p-hydroxyphenylglycine was crystallized. The concentrated solution was filtered while hot at 80 °C, and the filter cake was rinsed with a small amount of purified water at 80 °C. This resulted in 96 g of D-p-hydroxyphenylglycine with a yield of 10.7%, a content of 98.9%, and a specific optical rotation of -157° (c = 1, 1N HCl).

[0071] Then, the mother liquor remaining after the separation of D-p-hydroxyphenylglycine was cooled to 10 °C, and ammonium chloride was crystallized. The ammonium chloride was collected by filtration, resulting in 1200 g of ammonium chloride with a yield of 15.2%. The three mother liquors 3.2 L were collected, and the concentration of D-p-hydroxyphenylglycine was 22 g / L, the concentration of ammonium chloride was 278 g / L, the pH was 4.9, and the conductivity was 339 ms / cm.

[0072] In summary, without considering the use of the three recovered mother liquors and the washing solution, the total yield of D-p-hydroxyphenylglycine was 84.1% with a content of greater than 98.9%, and the total yield of ammonium chloride was 77.3%.

Claims

1. A method for recovering D-p-hydroxyphenylglycine and ammonium chloride from a crystallization mother liquor, the method comprising the following steps: (1) primary recovery of D-p-hydroxyphenylglycine and ammonium chloride The crystallization mother liquor of enzymatic synthesis of D-p-hydroxyphenylglycine is subjected to ultrafiltration using an ultrafiltration membrane to obtain an ultrafiltrated mother liquor; the ultrafiltrated mother liquor is then concentrated to 2-4 times at a temperature of 50-90°C by means of reduced pressure distillation, and D-p-hydroxyphenylglycine is crystallized out, and the mother liquor is filtered at this temperature to obtain D-p-hydroxyphenylglycine and the filtered mother liquor; the filtered mother liquor is cooled to a temperature of 5-25°C, and ammonium chloride is crystallized out, and the mother liquor is filtered at this temperature to obtain ammonium chloride and the filtered primary mother liquor; (2) secondary recovery of D-p-hydroxyphenylglycine and ammonium chloride The primary mother liquor obtained in step (1) is concentrated to 1.5-2.5 times at a temperature of 50-90°C by means of reduced pressure distillation, and D-p-hydroxyphenylglycine is crystallized out, and the mother liquor is filtered at this temperature to obtain D-p-hydroxyphenylglycine and the filtered mother liquor; the filtered mother liquor is cooled to a temperature of 5-25°C, and ammonium chloride is crystallized out, and the mother liquor is filtered at this temperature to obtain ammonium chloride and the filtered secondary mother liquor. wherein In the crystallization mother liquor of enzymatic synthesis of D-p-hydroxyphenylglycine, the concentration of D-p-hydroxyphenylglycine is 15-20 g / L, the concentration of ammonium chloride is 140-160 g / L, the pH value is 4.5-5.5, and the conductivity is 150-200 ms / cm.

2. The method for recovering D-p-hydroxyphenylglycine and ammonium chloride from crystallization mother liquor according to claim 1, characterized in that, in In step (1) of primary recovery of D-p-hydroxyphenylglycine and ammonium chloride, the ultrafiltration membrane used has a molecular weight cut-off of 1000-2500 Da.

3. The process for recovering D-p- hydroxyphenylglycine and ammonium chloride from a crystallization mother liquor according to claim 1, characterized in that, in the step of crystallizing the D-p-hydroxyphenylglycine from the mother liquor, the mother liquor is cooled to a temperature of 40 to 60°C. In step (1) of primary recovery of D-p-hydroxyphenylglycine and ammonium chloride, the temperature during the concentration by reduced pressure distillation is kept in the range of 60-80°C, the vacuum degree is controlled to be ≤-0.080 MPa, and the ultrafiltrated mother liquor is concentrated to 2.5-4 times under reduced pressure.

4. The process of claim 1 for recovering D-p- hydroxyphenylglycine and ammonium chloride from a crystallization mother liquor, characterized in that, in the step of In step (1) of primary recovery of D-p-hydroxyphenylglycine and ammonium chloride, the filtered mother liquor is cooled to a temperature of 10-20°C, and ammonium chloride crystals are precipitated, and the precipitated ammonium chloride and the primary mother liquor are collected by filtration; in the obtained primary mother liquor, the concentration of D-p-hydroxyphenylglycine is 20-25 g / L, the concentration of ammonium chloride is 280-320 g / L, the pH value is 4.5-5.5, and the conductivity is 300-400 ms / cm.

5. The process of claim 1 for recovering D-p- hydroxyphenylglycine and ammonium chloride from a crystallization mother liquor, characterized in that, in the step of In step (2) of secondary recovery of D-p-hydroxyphenylglycine and ammonium chloride, the primary mother liquor obtained in step (1) is concentrated to 1.5-2.5 times at a temperature of 60-80°C by means of reduced pressure distillation, and D-p-hydroxyphenylglycine is crystallized out, and the mother liquor is filtered at this temperature to obtain D-p-hydroxyphenylglycine and the filtered mother liquor.

6. The process of claim 1 wherein the process is further characterized by In the secondary recovery of D-p-hydroxyphenylglycine and ammonium chloride in step (2), the filtered mother liquor is cooled to 10-20°C, ammonium chloride crystals are precipitated, filtered, and the precipitated ammonium chloride and secondary mother liquor are collected; the concentration of D-p-hydroxyphenylglycine in the obtained secondary mother liquor is 20-25 g / L, the concentration of ammonium chloride is 280-320 g / L, the pH is 4.5-5.5, and the conductivity is 300-400 ms / cm; and as needed, the secondary mother liquor is pretreated and used in step (1) to be combined with the crystallization mother liquor of the enzymatic synthesis of D-p-hydroxyphenylglycine.

7. The process of claim 1, wherein the process is characterized by, The method further comprises tertiary recovery of D-p-hydroxyphenylglycine and ammonium chloride, i.e. step (3): the secondary mother liquor obtained in step (2) is concentrated to 1.5-2.5 times by vacuum distillation at a temperature of 50-90°C, D-p-hydroxyphenylglycine is precipitated, and the filtrate is obtained by filtration at this temperature; the filtrate is cooled to 5-25°C, ammonium chloride is precipitated, and the filtrate is obtained by filtration at this temperature; and the ammonium chloride and the tertiary mother liquor are obtained.

8. The process of claim 7, wherein the process is characterized by, In step (3), the secondary mother liquor obtained in step (2) is concentrated to preferably 1.5-2.5 times by vacuum distillation at a temperature of 60-80°C and a vacuum degree of ≤-0.080 MPa, D-p-hydroxyphenylglycine is precipitated, and the filtrate is obtained by filtration at this temperature; and as needed, the D-p-hydroxyphenylglycine filter cake is rinsed with purified water at 60-80°C.

9. The process of claim 8, wherein the process is characterized by, In step (3), the filtrate is cooled to 10-20°C, ammonium chloride crystals are precipitated, filtered, and the precipitated ammonium chloride and tertiary mother liquor are collected; and as needed, the washing water collected after rinsing the D-p-hydroxyphenylglycine filter cake and the tertiary mother liquor are pretreated and used in step (1) to be combined with the crystallization mother liquor of the enzymatic synthesis of D-p-hydroxyphenylglycine.

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